Molecular-targeted cancer therapeutics have shown impressive activity in the clinic. Some of the best noted examples include the tyrosine kinase inhibitors imatinib in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) or KIT/PDGFR-mutant gastrointestinal stromal tumors (GISTs) and erlotinib in EGFR-mutant non-small cell lung cancer (NSCLC) (Krause, D. S. and R. A. Van Etten (2005) N. Engl. J. Med. 353(2):172-187). Treatment with these agents has led to dramatic anti-tumor responses in patient populations harboring these molecular abnormalities. However, despite the impressive initial clinical responses, most patients eventually progress due to the acquisition of drug resistance (Engelman, J. A. and J. Settleman (2008) Curr. Opin. Genet. Dev. 18(1):73-79). Identification of mechanisms of resistance have consequently opened the door to more rational drug combinations and the development of “second-generation” inhibitors that can potentially overcome or avoid the emergence of resistance.
Medulloblastoma is a primitive neuroectodermal tumor of the cerebellum that represents the most common brain malignancy in children (Polkinghorn, W. R. and N. J. Tarbell (2007) Nat. Clin. Pract. Oncol. 4(5):295-304). Despite improvements in survival rates, the debilitating side effects of adjuvant radiation represent a major clinical challenge, thus supporting the need for new molecular targeted therapies.
The Hedgehog (Hh) signaling pathway has been directly implicated in the pathogenesis of medulloblastoma. Constitutive Hh signaling, most often due to underlying loss of function mutations in the inhibitory receptor PTCH1, has been demonstrated in approximately 30% of sporadic cases (Zurawel, R. H. et al. (2000) Genes Chromosomes Cancer 27(1):44-51; Kool, M. et al. (2008) PLoS ONE 3(8):e3088; Dellovade, T. et al. (2006) Annu. Rev. Neurosci. 29:539; Rubin, L. L. and F. J. de Sauvage (2006) Nat. Rev. Drug Discov. 5:1026). Mice heterozygous for Ptchl (Ptch1+/−) can spontaneously develop medulloblastoma and treatment with Hh pathway inhibitors results in tumor elimination and prolonged survival (Goodrich, L. V. et al. (1997) Science 277(5329):1109-1113; Romer, J. T. et al. (2004) Cancer Cell 6(3):229-240). However, it has recently been observed that a patient treated with the novel Hh pathway inhibitor, GDC-0449 initially showed a dramatic response to treatment (Charles M. Rudin et al. (2009) N. Engl. J. Med. (submitted)), only to fail to have a durable response to treatment and a relapse of the tumor.
There is an urgent need in the art to find compounds that modulate SMO activity in such mutant SMO proteins to overcome drug resistance upon treatment with GDC-0449. There is further a need to a method to diagnose patients who may be resistant to treatment either through natural variation of their SMO genotype or through acquired mutation and resistance.